Abstract:

The present invention relates generally to treatment of muscle pain and/or
fatigue and to methods for treatment of side effects of statin therapy.
In particular, the invention relates to the use of certain substituted
benzoquinones, e.g. Coenzymes Q, particularly Coenzyme Q10 (Q10), in
therapy. The invention also relates to the use of Q10 in combinative
therapy with other agents such as uridine, its biological precursors or
salts, esters, tautomers or analogues thereof ("uridine related
compounds"). The invention is also directed to compositions, uses and
combination packs or kits related to the treatment methods.
In a preferred aspect the invention relates to a method of treatment of
one or more side effects of statin therapy comprising administering to a
subject in need of such treatment an effective amount of uridine, one of
its biological precursors or a salt, ester, tautomer or analogue thereof
either simultaneously, sequentially or separately to administration of an
effective amount of at least one compound of Formula (I).

Claims:

1. A method of treatment of one or more side effects of statin therapy
comprising administering to a subject in need of such treatment an
effective amount of uridine, one of its biological precursors or a salt,
ester, tautomer or analogue thereof either simultaneously, sequentially
or separately to administration of an effective amount of at least one
compound of Formula (I) ##STR00004## whereinR1 is selected from H or
C1-16 alkylR2 and R3 are each independently selected from
II, hydroxy, C1-16 alkyl, C1-6 alkoxy, C1-6 alkenyl,
C1-6 alkenoxy, C1-6 alkynyl or C1-6 alkynoxy; andR4
is alkyl, alkenyl, alkoxy, alkenoxy, alkylol or alkenylol.

2. The method according to claim 1 wherein said side effect is one or more
of rhabdomyolysis, headache, joint pain, fever, muscle pain, back pain,
abdominal cramping, sleep disorder, rhinitis, sinusitis, stimulation of
coughing reflex, dizziness and fatigue.

3. The method according to claim 1 wherein said side effect is muscle
pain.

4. The method according to claim 1 wherein the compound of Formula (I) is
Coenzyme Q10.

5. The method according to claim 1 wherein the uridine precursor is orotic
acid or a salt, ester, tautomer or analogue thereof.

6. The method according to claim 1 wherein the salt of a uridine precursor
is magnesium orotate.

7. A method of treatment of one or more side effects of statin therapy
comprising administering to a subject in need of such treatment an
effective amount of magnesium orotate either simultaneously, sequentially
or separately to administration of an effective amount of Coenzyme Q10,
optionally in association with one of more pharmaceutically acceptable
additives.

8. The method according to claim 7 wherein said side effect is one or more
of rhabdomyolysis, headache, joint pain, fever, muscle pain, back pain,
abdominal cramping, sleep disorder, rhinitis, sinusitis, stimulation of
coughing reflex, dizziness and fatigue.

9. The method according to claim 7 wherein said side effect is muscle
pain.

10. Use of uridine, one of its biological precursors or a salt, ester,
tautomer or analogue thereof and at least one compound of Formula (I)
##STR00005## whereinR1 is selected from H or C1-16 alkylR2
and R3 are each independently selected from H, hydroxy, C1-16
alkyl, C1-6 alkoxy, C1-6 alkenyl, C1-6 alkenoxy, C1-6
alkynyl or C1-6 alkynoxy; andR4 is alkyl, alkenyl, alkoxy,
alkenoxy, alkylol or alkenylol;in preparation of a medicament for
treatment of one or more side effects of statin therapy.

11. The use according to claim 10 wherein said side effect is one or more
of rhabdomyolysis, headache, joint pain, fever, muscle pain, back pain,
abdominal cramping, sleep disorder, rhinitis, sinusitis, stimulation of
coughing reflex, dizziness and fatigue.

12. The use according to claim 10 wherein said side effect is muscle pain.

13. The use according to claim 10 wherein the compound of Formula (I) is
Coenzyme Q10.

14. The use according to claim 10 wherein the uridine precursor is orotic
acid or a salt, ester, tautomer or analogue thereof.

15. The use according to claim 10 wherein the salt of a uridine precursor
is magnesium orotate.

16. Use of magnesium orotate, Coenzyme Q10 and optionally one or more
pharmaceutically acceptable additives in preparation of a medicament for
treatment of one or more side effects of statin therapy.

17. The use according to claim 16 wherein said side effect is one or more
of rhabdomyolysis, headache, joint pain, fever, muscle pain, back pain,
abdominal cramping, sleep disorder, rhinitis, sinusitis, stimulation of
coughing reflex, dizziness and fatigue.

18. The use according to claim 16 wherein said side effect is muscle pain.

19. A composition comprising uridine, one of its biological precursors or
a salt, ester, tautomer or analogue thereof and at least one compound of
Formula (I) ##STR00006## whereinR1 is selected from H or C1-16
alkylR2 and R3 are each independently selected from H, hydroxy,
C1-16 alkyl, C1-6 alkoxy, C1-6 alkenyl, C1-6
alkenoxy, C1-6 alkynyl or C1-6 alkynoxy; andR4 is alkyl,
alkenyl, alkoxy, alkenoxy, alkylol or alkenylol.

20. The composition according to claim 19 further comprising at least one
statin.

21. The composition according to claim 20 wherein the at least one statin
is selected from atorvastatin, simvastatin, pravastatin, lovastatin,
cerivastatin and fluvastatin.

22. The composition according to claim 19 wherein the compound of Formula
(I) is Coenzyme Q10.

23. The composition according to claim 19 wherein the uridine precursor is
orotic acid or a salt, ester, tautomer or analogue thereof.

24. The composition according to claim 19 wherein the salt of a uridine
precursor is magnesium orotate.

25. The composition according to claim 19 further comprising one or more
pharmaceutically acceptable additives.

26. A composition comprising magnesium orotate, Coenzyme Q10 and
optionally one or more pharmaceutically acceptable additives.

27. The composition according to claim 26 further comprising at least one
statin.

28. The composition according to claim 27 wherein the at least one statin
is selected from atorvastatin, simvastatin, pravastatin, lovastatin,
cerivastatin and fluvastatin.

29. A combination pack or kit comprising uridine, one of its biological
precursors or a salt, ester, tautomer or analogue thereof and at least
one compound of Formula (I) ##STR00007## whereinR1 is selected from
H or C1-16 alkylR2 and R3 are each independently selected
from H, hydroxy, C1-16 alkyl, C1-6 alkoxy, C1-6 alkenyl,
C1-6 alkenoxy, C1-6 alkynyl or C1-6 alkynoxy; andR4
is alkyl, alkenyl, alkoxy, alkenoxy, alkylol or alkenylol;wherein said
pack or kit is adapted for the simultaneous, sequential or separate
administration of the uridine, one of its biological precursors or a
salt, ester, tautomer or analogue thereof and the compound of Formula
(I).

30. The combination pack or kit according to claim 29 wherein the compound
of Formula (I) is Coenzyme Q10.

31. The combination pack or kit according to claim 29 wherein the uridine
precursor is orotic acid or a salt, ester, tautomer or analogue thereof.

32. The combination pack or kit according to claim 29 wherein the salt of
a uridine precursor is magnesium orotate.

33. A combination pack or kit comprising at least one statin, uridine, one
of its biological precursors or a salt, ester, tautomer or analogue
thereof and at least one compound of Formula (I) ##STR00008##
whereinR1 is selected from H or C1-16 alkylR2 and R3
are each independently selected from H, hydroxy, C1-16 alkyl,
C1-6 alkoxy, C1-6 alkenyl, C1-6 alkenoxy, C1-6
alkynyl or C1-6 alkynoxy; andR4 is alkyl, alkenyl, alkoxy,
alkenoxy, alkylol or alkenylol;wherein said pack or kit is adapted for
the simultaneous, sequential or separate administration of the statin,
uridine, one of its biological precursors or a salt, ester, tautomer or
analogue thereof and the compound of Formula (I).

34. The combination pack or kit according to claim 33 wherein the at least
one statin is selected from atorvastatin, simvastatin, pravastatin,
lovastatin, cerivastatin and fluvastatin.

35. The combination pack or kit according to claim 33 wherein the compound
of Formula (I) is Coenzyme Q10.

36. The combination pack or kit according to claim 33 wherein the uridine
precursor is orotic acid or a salt, ester, tautomer or analogue thereof.

37. The combination pack or kit according to claim 33 wherein the salt of
a uridine precursor is magnesium orotate.

38. A combination pack or kit comprising at least one statin, magnesium
orotate and Coenzyme Q10 wherein said pack or kit is adapted for the
simultaneous, sequential or separate administration of the statin,
magnesium orotate and Coenzyme Q10.

39. The combination pack or kit according to claim 38 wherein the at least
one statin is selected from atorvastatin, simvastatin, pravastatin,
lovastatin, cerivastatin and fluvastatin.

40. A method of treatment of muscle pain and/or fatigue comprising
administering to a subject in need of such treatment an effective amount
of at least one compound of Formula (I) ##STR00009## whereinR1 is
selected from H or C1-16 alkylR2 and R3 are each
independently selected from H, hydroxy, C1-6 alkyl, C1-6
alkoxy, C1-6 alkenyl, C1-6 alkenyloxy, C1-6 alkynyl or
C1-6 alkynyloxy; andR4 is alkyl, alkenyl, alkoxy, alkylol or
alkenylol.

41. The method according to claim 40 wherein the compound of Formula (I)
is Coenzyme Q10.

42. The method according to claim 40 further involving administration to
said subject an effective amount of uridine, one of its biological
precursors or a salt, ester, tautomer or analogue thereof.

43. The method according to claim 40 further involving administration to
said subject of an effective amount of orotic acid or a salt, ester,
tautomer or analogue thereof.

44. The method according to claim 40 further involving administration to
said patient of an effective amount of magnesium orotate.

45. A method of treatment of a side effect of a drug therapy comprising
administering to a subject in need of such treatment an effective amount
of at least one compound of Formula (I) ##STR00010## whereinR1 is
selected from H or C1-16 alkylR2 and R3 are each
independently selected from H, hydroxy, C1-6 alkyl, C1-6
alkoxy, C1-6 alkenyl, C1-6 alkenyloxy, C1-6 alkynyl or
C1-6 alkynyloxy; andR4 is alkyl, alkenyl, alkoxy, alkylol or
alkenylol.

46. The method according to claim 45 wherein the compound of Formula (I)
is Coenzyme Q10.

47. The method according to claim 45 further involving administration to
said subject an effective amount of uridine, one of its biological
precursors or a salt, ester, tautomer or analogue thereof.

48. The method according to claim 45 further involving administration to
said subject of an effective amount of orotic acid or a salt, ester,
tautomer or analogue thereof.

49. The method according to claim 45 further involving administration to
said patient of an effective amount of magnesium orotate.

50. The method of treatment according to claim 45 wherein the drug therapy
is a therapy for hypercholesterolemia, is a therapy for hyperlipidemia,
is a corticosteroid therapy or is a cancer chemotherapy.

Description:

CROSS REFERENCE TO RELATED APPLICATION

[0001]The present application is a continuation application of U.S. Ser.
No. 10/433,074, filed May 29, 2003, the entire contents of which are
incorporated herein by reference.

FIELD OF THE INVENTION

[0002]The present invention relates generally to treatment of muscle pain
and/or fatigue and to methods for treatment of side effects of statin
therapy. In particular, the invention relates to the use of certain
substituted benzoquinones, e.g. Coenzymes Q, particularly Coenzyme Q10
(Q10), in therapy. The invention also relates to the use of Q10 in
combinative therapy with other agents such as uridine, its biological
precursors or salts, esters, tautomers or analogues thereof ("uridine
related compounds"). The invention is also directed to compositions, uses
and combination packs or kits related to the treatment methods.

BACKGROUND TO THE INVENTION

[0003]There are numerous drug therapies such as AZT, corticosteroids,
cancer chemotherapeutic agents and hypercholesterolemic drugs, which are
known to give rise to potentially serious side effects. These effects can
be disabling and may last for the duration of the causative drug
treatment or even after the drug treatment is complete, affecting not
only an individual's capacity to work but also perform the simple tasks
involved in day to day life. One particular group of drugs for which side
effects are well recognised is the statins which are commonly used to
treat hypercholesterolemia, a major cause of cardiovascular disease.

[0004]Cardiovascular disease is a term that encompasses a broad range of
diseases and syndromes relating to the impairment of function of the
heart and its associated network of blood vessels within the body. In
spite of decades of declining death rate in the developed world,
cardiovascular disease is still the single most common cause of death
accounting for about one third of all deaths in the United States in
1997. Cardiovascular disease has many causes and is characterised by
complex interactions between the heart, blood vessels, peripheral organs
and the tissues. Some types of cardiovascular disease such as coronary
heart disease or stroke can occur acutely and without warning, often with
severe consequences, including death. Medically these are managed with
aggressive treatment (drugs and surgery) followed by chronic treatment to
prevent recurrence. Other types of cardiovascular disease such as
hypertension (high blood pressure) and hyperlipidemia (high cholesterol)
progress slowly, often without overt symptoms, and must be managed by
diet and long-term chronic drug therapy.

[0005]Although cholesterol is an essential component of a healthy
functioning body, being required for the formation of functional
membranes, steroid hormones and bile acids, excessive levels,
particularly when associated with low density lipoproteins (LDLs),
constitute a health risk. It is well established that there is a cause
and effect relationship between hypercholesterolemia (excessive blood
cholesterol levels) and disease and mortality from coronary artery
(heart) disease. Of the deaths resulting from cardiovascular disease,
more than three quarters can be attributed to atherosclerosis and its
complications.

[0006]Atherosclerosis is a generalized disease of the arteries that
develops in a symptom free manner over many years. The most common
outcome of atherosclerosis is coronary heart disease, followed by stroke
and peripheral vascular disease. Elevated blood cholesterol concentration
is a major contributing factor in the development of atherosclerosis. In
situations of excessive blood cholesterol levels, cholesterol is
gradually deposited on the artery walls together with other fats,
resulting in build up which disrupts the free flow of blood, with
potentially severe results. To lower high cholesterol levels, patients
are treated with a range of drugs, commonly known as the statins, which
include atorvastatin, simvastatin, pravastatin, lovastatin, cerivastatin
and fluvastatin. These act to decrease cholesterol blood/tissue levels.

[0007]The statins have also recently been reported to have potential
utility in the treatment of dementia (The Lancet, 2000: 356; 1627-1631)
and various cancers, e.g. prostate, skin, lung colon, bladder, uterus and
kidney (Arch. Intern. Med. 2000, 160: 2363-2368).

[0008]However, there are a number of potentially serious side effects
associated with statin therapy, including rhabdomyolysis, headache, joint
pain, fever, muscle pain, back pain, abdominal cramping, sleep disorder,
rhinitis, sinusitis, stimulation of coughing reflex, dizziness and
fatigue. Of the contraindications for this group of drugs, two of the
most common are fatigue and/or muscle pain (often referred to as
"myalgia"). In severe cases, to these symptoms may lead to the
undesirable cessation of the vital therapy. In rare cases, severe muscle
wastage (rhabdomyolysis) has been reported. The risk of adverse side
effects during treatment with the statins is increased with concurrent
administration of certain other drugs, such as cyclosporin, fibric acid
derivatives (e.g. gemfibrozil), erthyromycin, niacin or other
antifungals. Similar symptoms to those experienced by patients undergoing
statin therapy may also be experienced by patients undergoing therapy
with other drugs, or may be experienced as a result of a disease state.

[0009]Thus, there exists a need for the treatment of muscle pain and
fatigue generally and especially for treatment of side effects associated
with certain drug therapies, particularly the side effects associated
with statin therapy.

[0010]It has now been found that certain substituted benzoquinones, such
as Coenzymes Q, particularly Q10, can be used in treating muscle pain and
fatigue and for treating adverse side effects associated with some drug
therapies. In particular, reversal or prevention of adverse statin
therapy related side effects can be achieved by administering certain
substituted benzoquinones simultaneously, sequentially or separately to
administration of uridine, its biological precursors or a salt, ester,
tautomer or analogue thereof. These compounds can therefore provide a
useful adjunctive therapy to certain drug therapies.

SUMMARY OF THE INVENTION

[0011]According to one embodiment of the present invention there is
provided a method of treatment of one or more side effects of statin
therapy comprising administering to a subject in need of such treatment
an effective amount of uridine, one of its biological precursors or a
salt, ester, tautomer or analogue thereof either simultaneously,
sequentially or separately to administration of an effective amount of at
least one compound of Formula (I)

[0016]According to another embodiment of the present invention there is
provided a method of treatment of one or more side effects of statin
therapy comprising administering to a subject in need of such treatment
an effective amount of magnesium orotate either simultaneously,
sequentially or separately to administration of an effective amount of
Coenzyme Q10, optionally in association with one of more pharmaceutically
acceptable additives.

[0017]In a further embodiment of the present invention there is provided
use of uridine, one of its biological precursors or a salt, ester,
tautomer or analogue thereof and at least one compound of Formula (I) in
preparation of a medicament for treatment of one or more side effects of
statin therapy.

[0018]In a still further embodiment of the invention there is provided use
of magnesium orotate, Coenzyme Q10 and optionally one or more
pharmaceutically acceptable additives in preparation of a medicament for
treatment of one or more side effects of statin therapy.

[0019]In another embodiment of the invention there is provided a
composition comprising uridine, one of its biological precursors or a
salt, ester, tautomer or analogue thereof and at least one compound of
Formula (I).

[0020]In a further embodiment of the present invention there is provided a
composition comprising magnesium orotate, Coenzyme Q10 and optionally one
or more pharmaceutically acceptable additives.

[0021]In a still further embodiment of the invention there is provided a
combination pack or kit comprising uridine, one of its biological
precursors or a salt, ester, tautomer or analogue thereof and at least
one compound of Formula (I) wherein said pack or kit is adapted for the
simultaneous, sequential or separate administration of the uridine, one
of its biological precursors or a salt, ester, tautomer or analogue
thereof and the compound of Formula (I).

[0022]In another embodiment of the invention there is provided a
combination pack or kit comprising at least one statin, uridine, one of
its biological precursors or a salt, ester, tautomer or analogue thereof
and at least one compound of Formula (I) wherein said pack or kit is
adapted for the simultaneous, sequential or separate administration of
the statin, uridine, one of its biological precursors or a salt, ester,
tautomer or analogue thereof and the compound of Formula (I).

[0023]In another embodiment of the invention there is provided a
combination pack or kit comprising at least one statin, magnesium orotate
and Coenzyme Q10 wherein said pack or kit is adapted for the
simultaneous, sequential or separate administration of the statin,
magnesium orotate and Coenzyme Q10.

[0024]In a further embodiment of the invention there is provided a method
of treatment of muscle pain and/or fatigue comprising administering to a
subject in need of such treatment an effective amount of at least one
compound of Formula (I).

[0025]In a still further embodiment of the invention there is provided a
method of treatment of a side effect of a drug therapy comprising
administering to a subject in need of such treatment an effective amount
of at least one compound of Formula (I). The drug therapy may be a
therapy for hypercholesterolemia, a therapy for hyperlipidemia, a
corticosteroid therapy or a cancer chemotherapy, for example.

BRIEF DESCRIPTION OF THE FIGURES

[0026]FIG. 1 graphically depicts the increasing absence of muscle pain in
a patient taking Q10 as determined over a 30 day period.

DETAILED DESCRIPTION OF THE INVENTION

[0027]Throughout this specification and the claims which follow, unless
the context requires otherwise, the word "comprise" and variations such
as "comprises" and "comprising" will be understood to imply the inclusion
of a stated integer or step or group of integers but not the exclusion of
any other integer or step or group of integers.

[0034]As used herein the term "alkynyl" denotes groups formed from
straight chain, branched or cyclic hydrocarbon residues containing at
least one carbon-carbon triple bond including ethynically mono-, di- or
poly- unsaturated alkyl or cycloalkyl groups as previously defined.
Unless the number of carbon atoms is specified the term preferably refers
to C1-20 alkynyl. Examples include ethynyl, 1-propynyl,
2-propynyl, butynyl isomers and pentynyl isomers.

[0035]The terms "alkoxy", "alkenoxy" and "alkynoxy" respectively denote
alkyl, alkenyl and alkynyl groups as hereinbefore defined when linked by
oxygen. The terms "alkylol" and "alkenylol" denote alkyl and alkenyl
groups, respectively, substituted in one or more positions by hydroxyl.

[0036]It will be appreciated that one or more compounds of formula (I) or
other compounds of the invention can have an asymmetric centre and
therefore can exist in more than one stereoisomeric form. The invention
extends to each of these forms individually and to mixtures thereof,
including racemates.

[0037]In a preferred form of the invention, in Formula (I) R1 is
hydrogen, methyl, ethyl or propyl, preferably hydrogen or methyl.

[0038]In another preferred form, R2 and R3 are independently
selected from II, C1-6 alkyl or C1-6 alkoxy, particularly H,
methyl, ethyl, propyl, methoxy, ethoxy or propoxy, preferably H, methyl
or methoxy. In another preferred form R2 and R3 are the same
and may both be H, methyl or methoxy.

[0039]In yet another preferred form of the invention, R4 is an
isoprenoid side chain of formula (a). Particularly preferred is a side
chain of formula (a) wherein n is 6 to 10. A preferred form is where n is
10.

[0040]Particularly preferred compounds are those where R1 is hydrogen
or methyl, and R2 and R3 are both hydrogen or methyl or
methoxy. Particularly preferred compounds are those where R1 is
methyl and R2 and R3 are both methoxy.

[0041]Another preferred class of compounds of Formula (I) are the Coenzyme
Q compounds, also known as the ubiquinones, which include Coenzymes Q6,
Q7, Q8, Q9, Q10 and Q11. A particularly preferred compound is Coenzyme
Q10, which may also be referred to as Coenzyme Q10 and which will be
referred to herein as Q10.

[0042]Compounds of Formula (I) may be commercially available (e.g. Q10) or
may be synthesised using methods known in organic chemistry or obtained
by microbiological means or may be derived from compounds obtained by any
one or more of these means.

[0043]By the phrase "uridine, its biological precursors or a salt, ester,
tautomer or analogue thereof" it is intended to embrace uridine and all
of those compounds which upon administration to a human or animal would
be converted in vivo to uridine or to a compound having equivalent
activity within the human or animal system to uridine. In vivo conversion
to uridine or to a compound having equivalent activity to uridine may
involve one or more chemical conversion steps. For convenience,
throughout this specification this class of compounds will be referred to
as "uridine related compounds". Clearly, within this class there are a
number of subclasses of uridine related compounds including biological
precursors of uridine or salts, esters, tautomers or analogues of these
biological precursors. As would be well understood by a skilled person
the term "biological precursor" is intended to define compounds would be
converted over one or more steps to uridine within a human or animal
system. Preferably the conversion will be over one to four steps,
preferably one or two steps. Some examples of biological precursors of
uridine include uridine monophosphate, uridine triphosphate, orotic acid,
dihydroorotate, triacetyl uridine and N-carbamoylaspartate. Salts of such
compounds with biologically acceptable cations such as ions of magnesium,
sodium, potassium, as well as tautomers, such as keto-enol tautomers and
esters of such compounds are also embraced by the invention. A
particularly preferred salt of orotic acid is magnesium orotate.

[0044]The methods and compositions of the invention may be used to treat
humans, mammals or other animal subjects. The invention is considered to
be particularly suitable for the treatment of human subjects. Non-human
subjects may include primates, livestock animals, domestic companion
animals and laboratory test animals.

[0045]The compounds of Formula (I) are administered in a treatment
effective amount. Reference herein to a treatment effective amount is
intended to include an amount which, when administered according to a
desired dosing regimen, will at least partially attain the desired
therapeutic effect or will inhibit, halt or otherwise delay the onset of
fatigue, muscle pain or a side effect of the drug treatment concerned.
The term "treatment" therefore embraces prophylactic treatments.

[0046]Dosing may occur at intervals of hours, days or weeks and may be
continued for as long as the desired therapeutic effect is maintained or
required. Suitable dosages and dosing regimens can be determined by an
appropriate health professional and may depend on the particular cause of
the side effect, the severity of the condition as well as the general
health, age and weight of the subject.

[0047]Suitable dosages of compounds of Formula (I) may lie within the
range of 10 mg to 4000 mg per day (i.e. per 24 hour period), such as 50
to 2000 mg per day. Particularly suitable dosages may lie in the range of
100 to 1000 mg per day. Preferably the compounds of Formula (I) are
administered from once to four times per day. Some exemplary
administration regimes are as follows: 1×200 mg, 1×250 mg,
1×300mg or 1×400mg per day, or twice a day, e.g. 2×100
mg, 2×150 mg or 2×200 mg. Dosage forms may be of any suitable
size (e.g. 10 mg, 50 mg or 100 mg). In one preferred embodiment of the
invention Q10 is administered twice a day as two doses each of 150 mg
(which could for example comprise 3×50 mg soft gel capsules) to
give a total administration of 300 mg per day.

[0048]Suitable dosages of uridine related compounds may lie within the
range of 10 mg to 10 g per day, such as 500 to 5 g per day. Particularly
suitable dosages may lie in the range of 1000 to 4000 mg per day.
Preferably the uridine or related compounds are administered from once to
four times per day. Some exemplary administration regimes are as follows:
1×800 mg, 1×1200 mg, 1×1600 mg or 1×2000 mg per
day, or twice a day, e.g. 2×400 mg, 2×600 mg, 2×800 mg
or 2×1000 mg. Dosage forms may be of any suitable size (e.g. 200
mg, 400 mg or 1000 mg). In one preferred embodiment of the invention
magnesium orotate is administered twice a day as two doses each of 800 mg
(which could for example comprise 2×400 mg tablets) to give a total
administration of 1600 mg per day.

[0049]The methods of the invention may be used to treat any type of muscle
fatigue or pain arising from certain conditions or diseases, surgery,
injury or as a side effect of certain drug therapies. Muscle pain and/or
fatigue associated with conditions or diseases such as CFS, fibromyalgia,
myofascial pain syndrome, viral infections, myolysis, rhabdomyolysis and
neuromuscular diseases may also be treated by the compounds of Formula
(I), preferably in conjunction with uridine related compounds.

[0050]One example of a group of therapeutic drugs characterised by side
effects treatable by the present invention is the statins, of which some
notable examples are atorvastatin, to simvastatin, pravastatin,
lovastatin, cerivastatin and fluvastatin. As indicated above, common side
effects associated with statin therapy include rhabdomyolysis, headache,
joint pain, fever, muscle pain, back pain, abdominal cramping, sleep
disorder, rhinitis, sinusitis, stimulation of coughing reflex, dizziness
and fatigue. Other examples of therapeutic drugs for which muscle fatigue
and/or pain or other symptoms treatable by the inventive methods may be a
side effect are AZT, hypercholesterolemia therapy drugs (apart from the
statins, such as bile acid binding agents such as cholestyramine and
colestipol or others such as niacin, probucol or HMG-CoA reductase
inhibitors which are not statins), hyperlipidemia therapy drugs,
corticosteroids and cancer chemotherapy drugs. Other specific examples of
drugs which may give rise to side effects treatable by methods of the
present invention are gemfibrozil, fenofibrate, ciprofibrate,
bezafibrate, betamethasone, cortisone, prednisolone, dexamethasone,
hydrocortisone, methylprednisolone, adriamycin, bleomycin, dactinomycin,
daunorubicin, doxorubicin, fludarabine, mitozantrone, epirubicin,
tamoxifen, goserelin, carboplatin, cisplatin and etoposide or their
salts, analogues or derivatives. Thus, the compounds of Formula (I),
particularly Q10, preferably combined with uridine related compounds, may
be a useful adjunctive treatment where drugs such as the statins, or
others are used to treat, for example, AIDS, hypercholesterolemia,
hyperlipidemia, dementia or cancers such as prostate, skin, lung, breast,
colon, bladder, uterus and kidney cancers.

[0051]The at least one compound of Formula (I) may also be administered in
conjunction (either separately, simultaneously or sequentially) with
other active agents and in particular with one or more further
anti-oxidant compound or compounds, such as Vitamin C or E, carotenoids
or carnitine, or their derivatives or analogues.

[0052]A compound of Formula (I) can be administered alone or in
combination with a uridine related compound and/or in conjunction with
the therapeutic drug (e.g. a statin compound) and optionally with a
further active agent or anti-oxidant. The combination of components
constituting the treatment may be administered either simultaneously (as
discrete dosage forms or as a single composition), sequentially, or
separated by a suitable time interval. Where the components are
administered as discrete dosage forms, i.e. not as intimate compositions,
each component may be administered in the same form or a different form,
e.g. oral, nasal, parenteral, rectal, vaginal or dermal. When the
compounds are administered simultaneously, sequentially or separately,
the components may be provided as discrete dosage forms. Optionally the
components of the combination may be provided in a kit form wherein the
kit is preferably in compartmentalised form adapted for the discrete
administration of the components.

[0053]Alternatively, when the components of the combination are
administered simultaneously, they may be provided as a single composition
containing the two or more components or may be provided in a kit form,
wherein the kit is compartmentalised for the simultaneous administration
of the components.

[0054]Where the compound of Formula (I), uridine related compound and/or
anti-oxidant or other active agent, and/or the therapeutic drug are
administered as discrete dosage forms, each may be formulated together
with one or more pharmaceutically acceptable additives to form
compositions. Where the components of the therapy are administered as a
single composition, the composition may also optionally comprise one or
more pharmaceutically acceptable additives.

[0055]The formulation of pharmaceutical compositions is well known to
those skilled in the art. Such compositions may contain any suitable
additives such as carriers, diluents or excipients, which are
pharmaceutically acceptable in the sense of being compatible with the
other ingredients of the composition and not injurious to the subject.
Suitable additives include all conventional solvents, oils, dispersion
media, fillers, solid carriers, coatings, antifungal and antibacterial
agents, dermal penetration agents (where appropriate), surfactants,
isotonic and absorption agents and the like. It will be understood that
the compositions of the invention may also include other supplementary
physiologically active agents. Further details of pharmaceutically
acceptable additives may be found in Remington's Pharmaceutical Sciences,
18th Edition, Mack Publishing Co., Easton, Pa., USA, the disclosure
of which is included herein in its entirety by way of reference.

[0056]The compositions may conveniently be presented in unit dosage form
and may be prepared by methods well known in the art of pharmacy. Such
methods include the step of bringing into association the active
ingredient with the carrier, which constitutes one or more accessory
ingredients. In general, the compositions are prepared by uniformly and
intimately bringing into association the active ingredient with liquid
carriers or finely divided solid carriers or both, and then if necessary
shaping the product.

[0057]The compounds and compositions of the invention may be presented for
oral administration (although other forms such as parenteral, rectal,
vaginal and dermal, may, under appropriate circumstances also be
contemplated) and may be presented as discrete units such as capsules,
sachets of powders or granules or tablets each containing a predetermined
amount of the active ingredient; as a powder or granules; as a solution
or a suspension in an aqueous or non-aqueous liquid; oils; paste; or as
an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. A
tablet may be made by compression or moulding, optionally with one or
more accessory ingredients. Compressed tablets may be prepared by
compressing in a suitable machine the active ingredient in a free-flowing
form such as a powder or granules, optionally mixed with a binder (e.g.
inert diluent, preservative disintegrant (e.g. sodium starch glycolate,
cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl
cellulose) surface-active or dispersing agent. Moulded tablets may be
made by moulding in a suitable machine a mixture of the powdered compound
moistened with an inert liquid diluent. The tablets may optionally be
coated or scored and may be formulated so as to provide slow or
controlled release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile. Tablets may optionally be provided with an
enteric coating, to provide release in parts of the gut other than the
stomach. The compounds may also be presented in the form of hard or soft
gelatin capsules

[0059]The compounds of the invention may also be presented for use in
veterinary compositions. These may be prepared by any suitable means
known in the art. Examples of such compositions include those adapted
for: [0060](a) oral administration, external application (e.g. drenches
including aqueous and non-aqueous solutions or suspensions), tablets,
boluses, powders, granules, pellets for admixture with feedstuffs, pastes
for application to the tongue; [0061](b) parenteral administration, e.g.
subcutaneous, intramuscular or intravenous injection as a sterile
solution or suspension [0062](c) topical application e.g. creams,
ointments, gels, lotions etc.

[0063]Those skilled in the art will appreciate that the invention
described herein is susceptible to variations and modifications other
than those specifically described. It is to be understood that the
invention includes all such variations and modifications which fall
within the spirit and scope of this general description. The invention
also includes all of the steps, features, compositions and compounds
referred to or indicated in this specification, individually or
collectively, and any and all combinations of any two or more of said
steps or features.

[0064]The invention will now be described with reference to the following
examples which are intended for the purpose of illustration only and are
not intended to limit the generality hereinbefore described.

Examples

Example 1

[0065]The patient, a white male aged approximately 54 years, had suffered
for a number of years from unexplained muscle pain which started in the
legs and gradually spread to other skeletal muscles. During the worst of
the symptoms, the patient was unable to raise his arms above his head and
was unable to drive a car. Walking was also difficult.

[0066]The patient was prescribed anti-inflammatory drugs and pain killers
which did not provide significant relief. The patient was eventually
diagnosed as suffering from a number of viral infections: cytomegalovirus
(CMV), Epstein-Barr virus (EBV) and hepatitis A.

[0067]The patient was started on a regimen of 150 mg per day of Coenzyme
Q10. Within several days the patient reported that the muscle pain had
subsided noticeably and his general sense of well being has improved. The
improvement was reported as permanent provided that the patient kept
taking Q10. On one occasion, the patient stopped taking the Q10 and the
muscle pain returned. When the patient recommenced the Q10 treatment, the
pain diminished within a short period.

Example 2

[0068]The patient, a white female aged approximately 44 years, had
suffered for a number of years from chronic fatigue syndrome. The
condition was severe enough such that she was unable to pursue her
teaching career and day to day tasks were generally performed with a
general sense of fatigue and muscle pain. Muscle pain was generally
controlled with over the counter (i.e. non-prescription) analgesics
containing 500 mg paracetamol and 8 mg codeine phosphate, 2-4 tablets per
day.

[0069]Table 1 provides a summary of the patient's self assessed levels of
general sense of well being, ability to perform day to day tasks and
level of (or relative absence of) muscle pain during a dosing regimen of
2×50 mg per day of Q10 (50 mg taken each at breakfast and dinner).
Levels were rated by the patient on a scale of 0-10, with 0 representing
severe incapacity or pain and 10 representing the complete absence of
pain or fatigue/excellent performance.

[0070]FIG. 1 depicts the self assessed (absence of) pain levels for the
patient, over a period of 30 days, on a scale of 1-10, where 0 is severe
pain and 10 relates to an absence of pain (wellness). On day 1 the
patient commenced taking 100 mg of Q10 per day until day 10 when the
dosage was increased to 200 mg per day

[0071]Table 2 outlines data for four patients (numbered #1-#4) undergoing
statin therapy for treatment of hypercholesterolemia and who had reported
suffering from varying levels of muscular pain and fatigue. This study is
ongoing, but the results below follow the study with these four patients
from week minus 1 (WK(-1)) to week plus 4 (WK(+4)).

[0072]Patients were either contacted or attended the clinic at weeks -1,
0, +1, +2 and +4. At the clinic on the first week (WK(-1)) details of the
patients' statin medication were recorded and daily doses were noted.
Patients were also scored for pain using the McGill Pain Questionnaire
(Melzack, R., 1975 "The McGill Pain Questionnaire: Major Properties and
Scoring Methods". Pain 1:277-299, the disclosure of which is included
herein in its entirety by way of reference) scales for Pain Rating Index
(PRI) and Present Pain Intensity (PPI). In the PRI index, which comprises
two scores, higher scores indicate increasing levels of pain. In the PPI
index present pain is given a score of 0 to 5, where 0 represents no pain
and 5 represents excruciating pain. Patients were also scored at WK(-1)
for fatigue using the Fatigue Impact Scale (Fisk, J. D. et al, 1994,
"Measuring the functional impact of fatigue: Initial Validation of the
Fatigue Impact Scale", Clinical Infectious Disease, 18 (Suppl 1):579-83,
the disclosure of which is included herein in its entirety by way of
reference). Questionnaires to determine PRI, PPI and FIS scores were
conducted thereafter at weeks +1, +2 and +4. At weeks +1 and +2 the
patients were contacted by telephone and were asked to mail their self
assessment questionnaires to the clinic.

[0074]It is to be noted that the normal range for blood creatine kinase
concentration is 0-200 units/L and the normal range for blood
concentration of alanine aminotransferase is 0-40 units/L.

[0075]Commencing at WK(0) and continuing through the study the patients
were asked to take a daily dose of 300 mg of Coenzyme Q10 (Q10), which
was administered as 3×50 mg soft gel capsules (commercially
available from R. P. Scherer), morning and evening.

[0076]The results of the parameters mentioned above are shown in Table 2.
Marginal decreases in PRI and FIS scores have been noted for a few
patients, although these decreases have not been of great significance.
It is possible that patient pain and fatigue measures may decrease with
prolonged treatment.

[0077]Table 3 outlines data for four patients (numbered #i-#iv) undergoing
statin therapy for treatment of hypercholesterolemia and who had reported
suffering from varying levels of muscular pain and fatigue. This study is
ongoing but the results below follow the study in relation to these four
patients from week minus 1 (WK(-1)) to week plus 4 (WK(+4)).

[0078]Patients were either contacted or attended the clinic at weeks -1,
0, +1, +2 and +4. On the first week at the clinic (WK(-1)) details of the
patients' statin medication were recorded and daily doses noted. Patients
were also scored for pain using the McGill Pain Questionnaire (Melzack,
R., 1975 "The McGill Pain Questionnaire: Major Properties and Scoring
Methods". Pain 1:277-299, the disclosure of which is included herein in
its entirety by way of reference) scales for Pain Rating Index (PRI) and
Present Pain Intensity (PPI). In the PRI index, which comprises two
scores, higher scores indicate increasing levels of pain. In the PPI
index present pain is given a score of 0 to 5, where 0 represents no pain
and 5 represents excruciating pain. Patients were also scored at WK(-1)
for fatigue using the Fatigue Impact Scale (Fisk, J. D. et al, 1994,
"Measuring the functional impact of fatigue: Initial Validation of the
Fatigue Impact Scale", Clinical Infectious Disease, 18 (Suppl 1):579-83,
the disclosure of which is included herein in its entirety by way of
reference). Questionnaires to determine PRI, PPI and FIS scores were
conducted thereafter at weeks +1, +2 and +4. At weeks +1 and +2 the
patients were contacted by telephone and were asked to mail their self
assessment questionnaires to the clinic.

[0080]Blood samples were taken at WK(0) and WK(+4) to determine individual
baseline levels of Q10 (Q10) (μg/ml) and thereby monitor patient
compliance. As with example 3, blood samples taken at WK(0) and WK(+4)
were also used to determine creatine kinase concentration (CK) (units/L)
and alanine aminotransferase concentration (ALT) (units/L), as well as
serum lipid levels. In patients #i-#iv the coadministration conducted did
not significantly affect statin therapy with respect to serum
cholesterol, HDL-cholesterol or LDL-cholesterol and triglyceride levels.

[0081]As can be seen from the results shown in Table 3 significant
improvements in PRI and PPI to pain scores and FIS fatigue score were
recorded in virtually all patients undergoing the combined therapy, which
would appear to demonstrate synergistic activity in treating pain and
fatigue, resulting from the combined administration of Q10 and magnesium
orotate.

[0082]It is to be noted that the normal range for blood creatine kinase
concentration is 0-200 units/L and the normal range for blood
concentration of alanine aminotransferase is 0-40 units/L.

[0083]Patient #i exhibited an abnormally high serum creatine kinase level
at WK(0), illustrative of muscle trauma (411 units/L). After four weeks
combined Q10 and magnesium orotate treatment the CK level fell to lie
within the normal range (181 units/L). These results highlight the
beneficial effects of the combination therapy on muscle trauma.